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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocytes (MO) and macrophages (MAC) are important producers of cytokines involved in the pathophysiology of bacterial sepsis. Most studies concentrate on the effects of bacterial lipopolysaccharides (LPS) regarding the induction of cytokine gene expression and secretion in MO/MAC. Here we report that besides LPS, the synthetic lipoprotein analogue lipopeptide N-palmitoyl-S-(2,3-bis(palmitoyl)-(2RS)-propyl)-(R)-cysteinyl-alanyl- glycine (Pam3-Cys-Ala-Gly), another component of the outer membrane of Gram-negative bacteria, as well as heat-killed Staphyloccocus aureus (S. aureus/SAC) are potent stimuli for cytokines in human MO. For all three investigated stimuli we found an individual pattern of cytokine induction: LPS was most potent in inducing interleukin-6 (IL-6) synthesis, whereas for tumour necrosis factor-alpha (TNF-alpha) secretion SAC was the best stimulus. Comparable amounts of IL-8 were induced by either LPS or Pam3-Cys-Ala-Gly, with SAC being less effective even at higher concentrations. The addition of serum led to an increase in LPS-, SAC- and Pam3-Cys-Ala-Gly-stimulated TNF-alpha secretion, indicating that the presence of serum is critical not just for LPS stimulation. Furthermore, as is known for LPS, Pam3-Cys-Ala-Gly and SAC rendered MO refractory to a second bacterial stimulus. Pam3-Cys-Ala-Gly and SAC induced tolerance for itself, but LPS could partially overcome this effect. As the CD14 molecule is discussed as a common receptor for different bacterial components, we investigated whether the TNF-alpha response of MO could be blocked by anti-CD14 antibodies. MY4, a CD14 antibody, selectively blocked the TNF-alpha secretion induced by LPS but not by Pam3-Cys-Ala-Gly or SAC. In summary, we conclude that besides LPS, lipopeptide Pam3-Cys-Ala-Gly and SAC are potent stimuli for human MO, while the mechanisms of activation seem to be partially different from LPS.
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PMID:A comparative analysis of cytokine production and tolerance induction by bacterial lipopeptides, lipopolysaccharides and Staphyloccous aureus in human monocytes. 948 14

Little is known about the role of peripheral blood mononuclear cells (PBMCs) in lipopolysaccharide (LPS) elimination. We studied the endotoxin elimination capacities (EEC) of PBMCs of 15 healthy volunteers, 13 patients with sepsis, and 1 patient suffering from paroxysmal nocturnal hemoglobinuria (PNH). Although expression of CD14, the best-characterized receptor for LPS to date, was reduced from 93.6% +/- 0.8% in healthy subjects to 50.5% +/- 6.5% in patients with sepsis and was 0.3% in a patient with septic PNH, EEC were found to be unchanged. There was no difference in the amount of tumor necrosis factor alpha (TNF-alpha) released by PBMCs of healthy donors and patients with sepsis. Anti-CD14 antibodies (MEM-18) completely suppressed EEC, binding of fluorescein isothiocyanate-labeled LPS to monocytes as determined by FACScan analysis, and TNF-alpha release in all three groups studied. The concentrations of soluble CD14 (sCD14) secreted by endotoxin-stimulated PBMCs from healthy donors and patients with sepsis amounted to 4.5 +/- 0.4 and 20.1 +/- 1.8 ng/ml, respectively. Based on our results, we suggest that PBMCs eliminate LPS by at least two different mechanisms; in healthy subjects, the membrane CD14 (mCD14) receptor is the most important factor for LPS elimination, while in patients with sepsis (including the septic state of PNH), increased sCD14 participates in LPS elimination. Secretion of sCD14 is strongly enhanced under conditions of low expression of mCD14 in order to counteract the reduction of mCD14 and maintain the function of monocytes. This sCD14 may substitute the role of mCD14 in LPS elimination during sepsis. The elimination of LPS by PBMCs correlates with the binding reaction and the secretion of TNF-alpha.
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PMID:Endotoxin binding and elimination by monocytes: secretion of soluble CD14 represents an inducible mechanism counteracting reduced expression of membrane CD14 in patients with sepsis and in a patient with paroxysmal nocturnal hemoglobinuria. 948 6

The identification of lipopolysaccharide binding protein (LBP) and CD14 as key molecules in the cellular response to endotoxin has been a major advance in unravelling the pathophysiological basis of Gram-negative sepsis. Much interest has focused on developing effective anti-endotoxin treatments to abrogate the inflammatory consequences of Gram-negative infection. The therapeutic options can be divided into those aimed at neutralizing or clearing circulating endotoxin, including anti-endotoxin antibodies and endotoxin neutralizing proteins, and those that antagonize the effects of endotoxin on human cells--for example, lipid A analogues. Initial experiences with anti-lipopolysaccharide antibodies have been disappointing but a new generation of anti-endotoxin agents is about to enter clinical trials. Whether these will prove sufficiently effective to reduce the morbidity and mortality of Gram-negative sepsis remains to be seen.
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PMID:Anti-endotoxin therapeutic options for the treatment of sepsis. 951 Oct 89

Meningococcal sepsis is a good model to study the dynamic response of cytokines and other soluble factors in vivo in the early stages of the disease. Levels of soluble CD14, interleukin-6 (IL-6), IL-6 receptor (IL-6R), and C-reactive protein (CRP) have been measured in plasma from 26 children with septic shock (nine of whom had disseminated intravascular coagulation) and from ten control children. All samples were collected at the onset, before treatment, and, when possible, 24 and 48 hours later. At admission, patients had significantly higher levels of IL-6 (p < 0.001) and CRP (p < 0.001), and lower levels of IL-6R (p < 0.005) than normal controls. After 24 hours, there was a significant increase of sCD24 (p < 0.05) and CRP (p < 0.001). Although IL-6 showed a progressive decline since the onset, its levels were always higher than controls. There was an inverse correlation between IL-6 and both IL-6R (p < 0.001) and CRP (p < 0.001), probably due to the later increase of CRP. Nevertheless, sCD14 did not correlate with IL-6 levels. We have confirmed the finding of IL-6 as a sensitive and reliable inflammatory marker in septic shock. Moreover, the ratio IL-6/IL-6R may have a prognostic value, given a putative role of IL-6R in modulating the effects of IL-6 in meningococcal sepsis.
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PMID:Lack of correlation between soluble CD14 and IL-6 in meningococcal septic shock. 955 85

LPS-binding protein (LBP) recognizes bacterial LPS and transfers it to CD14, thereby enhancing host cell stimulation, eventually resulting in pathogenic states such as septic shock. Recently, LBP also was shown to detoxify LPS by transferring LPS into HDL particles in vitro. Thus, the predominant in vivo function of LBP has remained unclear. To investigate the biological activity of acute phase concentrations of recombinant murine LBP, high concentrations of LBP were investigated in vitro and in vivo. Although addition of low concentrations of LBP to a murine macrophage cell line enhanced LPS-induced TNF-alpha synthesis, acute phase concentrations of LBP blocked this effect in comparison to low-dose LBP. When injected into mice intraperitoneally, LBP inhibited LPS-mediated cytokine release and prevented hepatic failure resulting in a significantly decreased mortality rate in LPS-challenged and D-galactosamine-sensitized mice, as well as in a murine model of bacteremia. These results complement a recent study revealing LBP-deficient mice to be dramatically more susceptible to an intraperitoneal Salmonella infection as compared with normal mice. We conclude that acute phase LBP has a protective effect against LPS and bacterial infection and may represent a physiologic defense mechanism against infection. Despite the limitations of any murine sepsis model, the results shown may imply that LBP could have beneficial effects during gram-negative peritonitis in humans.
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PMID:LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. 959 62

Macrophage activation by gram-negative lipopolysaccharide (LPS) has been extensively studied in an attempt to define the mechanisms that underlie innate immunity against bacterial pathogens. Dysregulation of these same mechanisms contributes to the pathophysiological consequences of bacterial sepsis. The biological actions of LPS are mediated, at least in part, by both LPS-binding proteins and LPS receptors. Several LPS receptors (CD14, the macrophage scavenger receptor, and the beta2 integrins), as well as the serum LPS-binding protein LBP, have been cloned and studied in detail. In addition, insights gained through the use of LPS antagonists have led to a better understanding of a molecule believed to function in conjunction with LPS receptors to transduce signals from the membrane to the cytosol. More recently, the use of knockout mice has greatly expanded our knowledge of the biology of LPS receptors and binding proteins. This review will summarize various phenotypes of mice that lack genes encoding CD14, the scavenger receptor, and LBP. These knockout mice have revealed several unexpected features of LPS action in vivo. Together, these animal models may provide a means to develop and evaluate novel therapeutic approaches to the control of endotoxin shock.
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PMID:LPS-binding proteins and receptors. 966 71

Lipopolysaccharide released during bacterial sepsis causes acute lung injury and ARDS. Pulmonary microvascular injury is a feature of ARDS, and vascular remodeling develops, leading to pulmonary hypertension. Pericytes in the lung circulation proliferate and contribute to the remodeling seen in experimental sepsis. It is unknown whether endotoxin can directly stimulate pericyte growth or induce contraction. We show that lipopolysaccharide from Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae increases rat lung pericyte proliferation in vitro by up to 72% on day 7 of exposure (P < 0.001), with E. coli being most potent. Lipid A is the active portion of the lipopolysaccharide, with equal activity at one-tenth the dose of lipopolysaccharide. Endotoxin's mitogenic effect requires the presence of serum, consistent with the requirement for a soluble CD14 receptor in the serum. Using FACS analysis, the pericytes lack surface CD14 receptors. Lipopolysaccharide exposure rapidly increases intracellular calcium and induces contraction of pericytes plated onto silicone membranes. Thus, endotoxin is a direct mitogen for lung pericytes in vitro and also induces pericyte contraction. Endotoxin, present in lung tissue early during sepsis, might directly contribute to the vascular remodeling in sepsis-induced lung injury.
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PMID:Effects of endotoxin on lung pericytes in vitro. 975 30

LPS-binding proteins in plasma play an important role in modifying LPS toxicity. Significant properties have already been attributed to the LPS-binding protein (LBP). It accelerates LPS toxicity as well as incorporation into high-density lipoproteins, leading to neutralization of LPS in serum. A search for other LPS-binding components in serum, using LPS-coated magnetic beads, revealed a new LPS-binding protein. N-terminal microsequencing identified this protein as serum amyloid P component (SAP). Purified SAP bound to smooth and rough types of LPS via the lipid A part. SAP inhibited the binding of FITC-labeled ReLPS (LPS from Salmonella minnesota strain R595) to human monocytes and the ReLPS-induced priming of the oxidative burst of human neutrophils only in the presence of low concentrations of LBP. In search for the LPS binding site of SAP, we found that pep27-39, a 13-mer peptide consisting of amino acids 27-39 of SAP, competitively inhibited the binding of LPS to SAP. In addition, pep27-39 significantly inhibited ReLPS-induced responses in phagocytes in the presence of serum, as well as in human whole blood. Carboxamidomethylated pep27-39 showed an even more pronounced reduction of the ReLPS-induced priming of phagocytes in human blood. Performing gel filtration of FITC-labeled ReLPS incubated with soluble CD14, we showed that SAP could not prevent binding of LPS to soluble CD14, in contrast to pep27-39. The ability of pep27-39 to antagonize specifically the effects of LPS in the complex environment of human blood suggests that pep27-39 may be a novel therapeutic agent in the treatment of gram-negative sepsis.
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PMID:A synthetic lipopolysaccharide-binding peptide based on amino acids 27-39 of serum amyloid P component inhibits lipopolysaccharide-induced responses in human blood. 975 83

The effect of lipopolysaccharide (LPS) on endothelial cells is a key component of the inflammatory response seen in Gram-negative sepsis. LPS does not cause death of cultured human endothelial cells. However, when the expression of new proteins is inhibited by cycloheximide, microvascular endothelial cells in culture undergo apoptosis. This finding suggests that LPS induces apoptotic and antiapoptotic pathways, with the antiapoptotic response being dependent on the synthesis of new proteins. Concurrent activation of apoptotic and antiapoptotic pathways has previously been documented for tumor necrosis factor (TNF). In the case of TNF, the antiapoptotic signal has been attributed to at least two cytoprotective proteins: the Bcl-2 homologue, A1, and the zinc-finger protein, A20. In this study, we demonstrate that both these molecules are induced in microvascular endothelial cells by LPS. Enforced overexpression of either A1 or A20 inhibits LPS and cycloheximide-initiated apoptosis. Induction of A1 and A20 does not require synthesis of intermediary proteins, but is dependent on the presence of soluble CD14. In addition, we show that inhibition of signaling by the transcription factor, NF-kappaB, blocks accumulation of A1 and A20 mRNA. Taken together, our findings suggest that LPS directly induces expression of the cytoprotective proteins, A1 and A20, via a CD14-dependent pathway requiring activation of NF-kappaB.
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PMID:Lipopolysaccharide induces the antiapoptotic molecules, A1 and A20, in microvascular endothelial cells. 976 60

Systemic injection of the bacterial endotoxin lipopolysaccharide (LPS) provides a very good mean for increasing the release of proinflammatory cytokines by circulating monocytes and tissue macrophages. There is now considerable evidence that LPS exerts its action on mononuclear phagocytes via the cell surface receptor CD14. The aim of the present study was to verify the hypothesis that the brain has also the ability to express the gene encoding the LPS receptor, which may allow a direct action of the endotoxin onto specific cellular populations during blood sepsis. Adult male Sprague-Dawley rats were sacrificed 1, 3, 6 and 24 h after systemic (i.v. or i.p.) injection of LPS or the vehicle solution. Brains were cut from the olfactory bulb to the medulla in 30-microm coronal sections and mRNA encoding rat CD14 was assayed by in situ hybridization histochemistry using a specific 35S-labeled riboprobe. The results show low levels of CD14 mRNA in the leptomeninges, choroid plexus and along blood vessels of the brain microvasculature under basal conditions. Systemic injection of the bacterial endotoxin caused a profound increase in the expression of the gene encoding CD14 within these same structures as well as in the circumventricular organs (CVOs) the organum vasculosum of the lamina terminalis, subfornical organ, median eminence and area postrema. In most of these structures, the signal for CD14 mRNA was first detected at 1 h, reached a peak at 3 h post-injection, declined at 6 h, and return to basal levels 24 h after LPS treatment. Quite interestingly, a migratory-like pattern of CD14 positive cells was observed from all sensorial CVOs to deeper parenchymal brain 3 and 6 h after LPS injection. At 6 h post-challenge, small positive cells were found throughout the entire parenchymal brain and dual-labeling procedure indicated that different cells of myeloid origin have the ability to express CD14 in response to systemic LPS. These included CVO microglia, choroid plexus and leptomeninge macrophages, parenchymal and perivascular-associated microglial cells, although specific nonmyeloid cells were also positive for the LPS receptor. These results provide the very first evidence of a direct role of LPS on specific cell populations of the central nervous system, which is likely to be responsible for the transcription of proinflammatory cytokines; first within accessible structures from the blood and thereafter through scattered parenchymal cells during severe sepsis.
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PMID:The bacterial endotoxin lipopolysaccharide has the ability to target the brain in upregulating its membrane CD14 receptor within specific cellular populations. 980 72


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